Method for the treatment of stroke using N-heterocyclic glyoxlyamide compounds

ABSTRACT

A method and composition for the treatment and/or prevention of stroke is disclosed using N-heterocyclic glyoxamide compounds having the following general formula:                    
     wherein X, E, F, R 11 , R 12 , R 14 , R 15 , R 16  and R 17  are as defined herein.

This is a 371 of PCT/JP98/01880 filed Apr. 23, 1998.

TECHNICAL FIELD

This invention relates to the use of N-heterocyclic glyoxylamidecompounds for the treatment of stroke.

BACKGROUND ART

This invention is directed to reducing or preventing nerve cell deathand subsequent neurological dysfunction normally occurring in a stroke.

Strokes are a major cause of death and disablement. Multiple mechanismsmay cause stroke. Hemorrhagic stroke occurs when rupture of an artery inthe brain causes a hemorrhage (viz., an aneurysm). Occlusive strokeoccurs when a thrombosis or embolism restrict blood flow to part of thebrain. For occlusive stroke the reduction of blood flow leads to deathof brain tissue. Thrombosis occurs when a blood clot forms and blocksblood flow in an artery supplying blood to the brain. Embolism occurswhen a moving clot settles in an artery supplying blood the brain,causing a stroke.

Many of those affected with strokes never recover full neurologicfunction or even a substantial measure of the neurologic functioninitially lost.

Conventional treatment consists of controlling blood pressure,administration, of blood thinners, and etc. None of the presently usedtechniques or therapeutic agents is without drawbacks. A great needremains to develop new methods of treating occlusive stroke by the useof improved therapeutic agents.

DISCLOSURE OF INVENTION

It is an object of this invention to provide a method of treatment of amammal, including a human, currently afflicted with a stroke orpreviously afflicted with a stroke, said method comprising administeringto said mammal a therapeutically effective amount of an N-heterocyclicglyoxylamide compound.

It is also an object of this invention to use an N-heterocyclicglyoxylamide compound for the manufacture of a medicament for treatingstroke in a mammal, including a human, currently afflicted with a strokeor previously afflicted with a stroke.

It is also an object of this invention to provide a composition fortreatment of a stroke in a mammal, including a human, currentlyafflicted with a stroke or previously afflicted with a stroke, saidcomposition comprising administering to said mammal a therapeuticallyeffective amount of an N-heterocyclic glyoxylamide compound.

It is also an object of this invention to provide a method of reducingthe occurrence of neuronal damage and associated neurologicaldysfunction in a stroke in a human compared to that which normallyoccurs by administering a therapeutically effective amount of anN-heterocyclic glyoxylamide compound.

It is also an object of this invention to use N-heterocyclicglyoxylamide compounds to reduce neurological degeneration such as canbe induced by a stroke and the associated functional impairment whichcan result in a human by administering a therapeutically effectiveamount of an N-heterocyclic glyoxylamide compound.

It is also an object of this invention to provide a composition ofreducing the occurrence of neuronal damage and associated neurologicaldysfunction in a stroke in a human compared to that which normallyoccurs by administering a therapeutically effective amount of anN-heterocyclic glyoxylamide compound.

The term “stroke” is used herein to mean occlusive stroke, e.g., anischemic event, resulting in the loss of oxygen supply to the braincaused by means inclusive of thrombosis or embolism.

The term, “subject” is used herein to mean mammals including humans.

BEST MODE FOR CARRYING OUT THE INVENTION

Treatment can be remedial or therapeutic as by administering anN-heterocyclic glyoxylamide compound following an ischemic event tomitigate the effects of that event. Treatment can also be prophylacticor prospective by administering a compound in anticipation that anischemic event may occur, for example, in a patient who is prone tostroke.

Cells known to be destroyed during a stroke include hippocampal neurons,cortical neurons, caudate and putaminous neurons, cerebellar neurons andbrain stem neurons. Since these hippocampal neurons are known to be themost sensitive to strokes, the therapeutically effective amount ofN-heterocyclic glyoxylamide compound is preferably a hippocampal neuronprotecting amount, i.e., an amount which reduces hippocampal neurondeath compared that which would occur if the stroke were untreated.

(A) Procedure for Subjects During or Soon After a Stroke:

Treatment for a subject currently afflicted with a stroke using themethod of the invention should occur within 6 hours of onset of thestroke, preferably within 4 hours, and most preferably as soon as strokediagnosis occurs. In order to obtain a rapid response with minimum risk,the administration of the N-heterocyclic glyoxylamide compound, forexample, 1H-indole-3-glyoxylamide compound or indolizine compound shouldpreferably be via a parenteral route in a neuronal cell protectingamount (i.e., an amount which reduces neuronal cell death compared tothat which would occur if the stroke were not treated).

In general, N-heterocyclic glyoxylamide compound will be administered toa mammal such as man so that an effective dose is received, for examplean intravenous dose in the range of about 0.1 to about 10 mg/kg of bodyweight.

(B) Procedure for Subjects in Danger of a Stroke:

Treatment of a subject for prevention of a stroke, where the subject isdetermined to be at a high risk for a stroke, but who does not currentlyhave a stroke, is to provide a level of N-heterocyclic glyoxylamidecompound such that on the occurrence of cerebral ischemia, there will besufficient N-heterocyclic glyoxylamide compound already present in thesubject to protect neuronal cells (i.e., an amount which would reduceneuronal cell death compared to that which would occur if a strokeoccurred and was untreated). Administration of N-heterocyclicglyoxylamide compound is preferably carried out orally on a daily basis.

Since the occurrence of ischemia could come at any time, therapeuticallysufficient plasma levels of N-heterocyclic glyoxylamide compound shouldbe present. In general, the plasma level of N-heterocyclic glyoxylamidecompound is a non-toxic concentration in the range of from about 0.01micromolar to 1000 micromolar. The amount administered to obtain suchplasma level depends on the method of administration and the half-lifeof the N-heterocyclic glyoxylamide compound. Preferably, administrationis on a daily basis so that the dose of N-heterocyclic glyoxylamidecompound can be minimized.

General Aspects of the Method:

It will be apparent to those skilled in the art that a compound of thepresent invention can be co-administered with other therapeutic orprophylactic agents and/or medicaments that are not medicallyincompatible therewith.

The regimen for treatment may stretch over many months or years so oraldosing is preferred for patient convenience and tolerance. With oraldosing, one to three oral doses per day, each from about 0.01 to about50 mg/kg of body weight are used with preferred doses being from about0.04 to about 5.0 mg/kg.

The specific dose of N-heterocyclic glyoxylamide compound administeredaccording to this invention to obtain therapeutic or prophylacticeffects will, of course, be determined by the particular circumstancessurrounding the case, including, for example, the compound administered,the route of administration, the size and age of the patient, theseverity of the stroke, and the condition being treated. Typical dailydoses will contain a non-toxic dosage level of from about 0.01 mg/kg toabout 50 mg/kg of body weight of an active compound of this invention.

Method of Administration.

This can be by any method such as parenteral or oral dosing wherein theN-heterocyclic glyoxylamide compound crosses the blood brain barrier insufficient amount to protect neuronal cells from death. TheN-heterocyclic glyoxylamide compounds are most often used in the methodof the invention in the form of pharmaceutical formulation, as describedinfra. Other forms of administration may be used in both human andveterinary contexts. Such alternative forms include the use ofsuppositories, transdermal patches, and compositions for buccal or nasaladministration, for example lozenges, nose drops, an aerosol spray, ortransdermal patch.

Compound Used in the Stroke Treatment Method

The method for treating subjects for the occurrence or prevention ofstroke comprises administering an effective amount of an N-heterocyclicglyoxylamide compound. Suitable 1H-indole-3-glyoxylamide compounds forthe practice of the method of treating and preventing stroke as taughtherein are those described in European Patent Application No.95302166.4, Publication No. 0 675 110 (publ., Oct. 4, 1995). Suitable1H-indole-3-glyoxylamide compounds are also those disclosed in U.S.patent application Ser. No. 08/469,954 filed Jun. 6, 1995, thedisclosure of which is incorporated herein by reference. Formulationscontaining these 1H-indole-3-glyoxylamide compounds and methods ofmaking them are also fully described in European Patent OfficePublication European Patent Application No. 95302166.4 and U.S. patentapplication Ser. No. 08/469,954. Suitable indolizine compounds aredisclosed in WO 9603383 (Publ., Feb. 8, 1996).

Definitions:

The words, “acid linker” refers to a divalent linking group symbolizedas, -(L_(a))- or -(La′)-, which has the function of joining the 4 or 5position of the indole nucleus or the 7 or 8 position of the indolizinenucleus to an acidic group in the general relationship:

The words, “acid linker length”, refer to the number of atoms (excludinghydrogen) in the shortest chain of the linking group -(L_(a))- or-(La′)- that connects the 4 or 5 position of the indole nucleus or the 7or 8 position of the indolizine nucleus with the acidic group.

The word “acidic group” is selected from -5-tetrazolyl, —SO₃H,

where n is from 1 to 8, R₈₉ is a metal or C1-C10alkyl, and R₉₉ ishydrogen or C1-C10 alkyl.

Preferred compounds for use in the method or composition of theinvention are those having the general formula (I) or a pharmaceuticallyacceptable salt, solvate or prodrug derivative thereof;

wherein;

E and F are differently C or N;

----- is presence or absence of a double bond;

each X is independently oxygen or sulfur;

R₁₁ is selected from groups (a), (b) and (c) where;

(a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl, C₇-C₂₀ alkynyl; or carbocyclicradical selected from the group cycloalkyl, cycloalkenyl, phenyl,naphthyl, norbornanyl, bicycloheptadienyl, tolyl, xylyl, indenyl,stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl,acenaphthyl, and anthryl, biphenylyl, bibenzylyl and related bibenzylylhomologues represented by the formula (bb),

 where n is a number from 1 to 8; or

(b) is a member of (a) substituted with one or more independentlyselected non-interfering substituents selected from the group consistingof C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₇-C₁₂ aralkyl, C₇-C₁₂alkaryl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, phenyl, tolyl, xylyl,biphenylyl, C₁-C₆ alkoxy, C₂-C₆ alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₁₂alkoxyalkyl, C₂-C₁₂ alkoxyalkyloxy, C₂-C₁₂ alkylcarbonyl, C₂-C₁₂alkylcarbonylamino, C₂-C₁₂ alkoxyamino, C₂-C₁₂ alkoxyaminocarbonyl,C₁-C₁₂ alkylamino, C₁-C₆ alkylthio, C₂-C₁₂ alkylthiocarbonyl, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₆ haloalkoxy, C₁-C₆haloalkylsulfonyl, C₂-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —C(O)O(C₁-C₆alkyl), —(CH₂)_(n)—O-(C₁-C₆ alkyl), benzyloxy, phenoxy, phenylthio,—CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy,—(CH₂)_(n)—CO₂H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino,hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro,phosphono, —SO₃H, thioacetal, thiocarbonyl, and C₁-C₆ carbonyl; where nis from 1 to 8;

(c) is the group -(L₁)-R₈₁; where, -(L₁)- is a divalent linking grouphaving the formula;

 where,

R₈₄ and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl,carboxy, carbalkoxy, or halo;

p is 1 to 5,

Z is a bond, —(CH₂)—, —O—, —N(C₁-C₁₀ alkyl)-, —NH—, or —S—; and whereR₈₁ is a group selected from (a) or (b);

R₁₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄cycloalkenyl, —O-(C₁-C₂ alkyl), or —S-(C₁-C₂ alkyl);

R₁₄ is hydrogen or a group, -(L_(a))-(acidic group) wherein -(L_(a))- isrepresented by the formula;

 where Q is selected from the group —(CH₂)—, —O—, —NH—, and —S—, and R₈₄and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl,aryl, C₁-C₁₀ alkaryl, C₁-C₁₀ aralkyl, and halo;

R₁₅ is hydrogen or a group, -(La′)-(acidic group) wherein -(La′)- isrepresented by the formula;

 where r is a number from 1 to 7, s is 0 or 1, and Q is selected fromthe group —(CH₂)—, —O—, —NH—, and —S—, and R_(84′) and R_(85′) are eachindependently selected from hydrogen, C₁-C₁₀ alkyl, aryl, C₁-C₁₀alkaryl, C₁-C₁₀ aralkyl, carboxy, carbalkoxy, and halo; provided that atleast one of R₁₄ or R₁₅ must be the group, -(La)-(acidic group) or-(La′)-(acidic group);

R₁₆ is hydrogen, carboxyl or ester thereof;

R₁₇ is selected from hydrogen, non-interfering substituents, selectedfrom the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₇-C₁₂ aralkyl, C₇-C₁₂ alkaryl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl,phenyl, tolyl, xylyl, biphenylyl, C₁-C₆ alkoxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₁₂ alkoxyalkyl, C₂-C₁₂ alkoxyalkyloxy, C₂-C₁₂alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino, C₂-C₁₂alkoxyaminocarbonyl, C₂-C₁₂ alkylamino, C₁-C₆ alkylthio, C₂-C₁₂alkylthiocarbonyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₆haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆ haloalkyl, C₁-C₆hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O-(C₁-C₆ alkyl),benzyloxy, phenoxy, phenylthio, —CHO, amino, amidino, bromo, carbamyl,carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal, thiocarbonyl,and C₁-C₆ carbonyl; where n is from 1 to 8.

A preferred class of compounds for the method or composition of theinvention are compounds represented by the formula (II):

wherein X, R₁₁, R₁₂, R₁₄, R₁₅, R₁₆ and R₁₇ are as defined above.

An alternatively preferred class of compounds for the method orcomposition of the invention are compounds represented by the formula(III):

wherein X, R₁₁, R₁₂, R₁₄, R₁₅, R₁₆ and R₁₇ are as defined above.

A further preferred class of compounds for the method or composition ofthe invention are the compounds represented by the formula (II) or (III)where both X's are oxygen, only one of R₁₄ or R₁₅ is -(L_(a))-(acidicgroup) or - (La′)-(acidic group ), and the acidic group is carboxyl.

Specific preferred compounds and all pharmaceutically acceptable salts,solvates and prodrug derivatives thereof which are useful in the methodor composition of the invention include the following:

(A)[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid,

(B)dl-2-[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoicacid,

(C)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid,

(D)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-3-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid,

(E)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid,

(F)[[3-(2-Amino-1,2-dioxoethyl)-1-[(2,6-dichlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]aceticacid,

(G)[[3-(2-Amino-1,2-dioxoethyl)-1-[(4-fluorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]aceticacid,

(H)[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-[(1-naphthyl)methyl]-1H-indol-4-yl]oxy]aceticacid,

(I)[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid,

(J)[[3-(2-Amino-1,2-dioxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]aceticacid,

(K)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]aceticacid,

(L)[[3-(2-amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]aceticacid,

(M)[[3-(2-Amino-1,2-dioxoethyl)-2-cyclopropyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid,

(N)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]aceticacid,

(O)4-[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoicacid,

(P) mixtures of (A) through (O),

(Q)[8-(Carbomethoxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,

(R)[3-Benzyl-8-(carbethoxymethyloxy)-2-ethylindolizin-1-yl]glyoxylamide,

(S)[8-(Carbethoxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,

(T)[3-Benzyl-8-(carbethoxymethyloxy)-2-methylindolizin-1-yl]glyoxylamide,

(U) [8-(Carbethoxymethyloxy)-3-(m-chlorobenzyl)-2-ethylindolizin-1-yl]glyoxylamide,

(V)[8-Carbethoxymethyloxy-2-ethyl-3-(1-naphthylmethyl)indolizin-1-yl]glyoxylamide,

(W)[3-Benzyl-8-(t-butoxycarbonylmethyloxy)-2-ethylindolizin-1-yl]glyoxylamide,

(X)[8-(Carbmethoxymethyloxy)-2-ethyl-3-(m-trifluoromethylbenzyl)indolizin-1-yl]glyoxylamide,

(Y)[8-(Carbmethoxymethyloxy)-2-cyclopropyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,

(Z) [3-Benzyl-8-(carboxymethyloxy)-2-ethylindolizin-1-yl]glyoxylamide,

(AA)[8-(Carboxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,

(BB) [3-Benzyl-8-(carboxymethyloxy)-2-methylindolizin-1-yl]glyoxylamide,

(CC)[8-(Carboxymethyloxy)-3-(m-chlorobenzyl)-2-ethylindolizin-1-yl]glyoxylamide,

(DD)[8-(Carboxymethyloxy)-2-ethyl-3-(m-trifluoromethylbenzyl)indolizin-1-yl]glyoxylamide,

(EE)[8-Carboxymethyloxy-2-ethyl-3-(1-naphthylmethyl)indolizin-1-yl]glyoxylamide,

(FF)[8-(Carboxymethyloxy)-2-cyclopropyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,

(GG) mixtures of (Q) through (FF).

Most preferred in the practice of the method or composition of theinvention are 1H-indole-3-glyoxylamides selected from the formula:

or indolizine-1-glyoxylamidles selected from the formula:

The salts of the above 1H-indole-3-glyoxylamide compounds represented bythe formula (II) and named compounds (A) through (P) and ofindolizine-1-glyoxylamide compounds represented by the formula (III) andnamed compounds (Q) through (GG) are particularly useful in the methodof the invention. In those instances where the 1H-indole-3-glyoxylamidecompounds and indolizine-1-glyoxylamide compounds possess acidic orbasic functional groups various salts may be formed which are more watersoluble and physiologically suitable than the parent compounds.Representative pharmaceutically acceptable salts, include but are notlimited to, the alkali and alkaline earth salts such as lithium, sodium,potassium, calcium, magnesium, aluminum and the like. Salts areconveniently prepared from the free acid by treating the acid insolution with a base or by exposing the acid to an ion exchange resin.

Included within the definition of pharmaceutically acceptable salts arethe relatively non-toxic, inorganic and organic base addition salts ofthe 1H-indole-3-glyoxylamide compounds and indolizine-1-glyoxylamidecompounds used in the method or composition of the present invention,for example, ammonium, quaternary ammonium, and amine cations, derivedfrom nitrogenous bases of sufficient basicity to form salts with thecompounds of this invention (see, for example, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Phar. Sci., 66: 1-19 (1977)). Moreover, basicgroup(s) present in the 1H-indole-3-glyoxylamide compound may be reactedwith suitable organic or inorganic acids to form salts such as acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride,edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate,gluconate, glutamate, glycolylarsanilate, hexylresorcinate, bromide,chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,laurate, malate, mandelate, mesylate, methylbromide, methylnitrate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate,pantothenate, phosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate,trifluoromethane sulfonate, and valerate.

Certain 1H-indole-3-glyoxylamide compounds and indolizine-1-glyoxylamidecompounds may possess one or more chiral centers and may thus exist inoptically active forms. Likewise, R- and S- isomers and mixturesthereof, including racemic mixtures as well as mixtures of cis- andtransisomers, are contemplated for use by the method or composition ofthis invention.

Prodrugs are derivatives of the 1H-indole-3-glyoxylamide compounds orindolizine-1-glyoxylamide compounds which have chemically ormetabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention which arepharmaceutically active in vivo. Derivatives of the1H-indole-3-glyoxylamide compounds and indolizine-1-glyoxylamidecompounds have activity in both their acid and base derivative forms,but the acid derivative form often offers advantages of solubility,tissue compatibility, or delayed release in a mammalian organism (see,Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam1985). Prodrugs include acid derivatives well known to practitioners ofthe art, such as, for example, esters prepared by reaction of the parentacidic compound with a suitable alcohol, or amides prepared by reactionof the parent acid compound with a suitable amine. Simple aliphatic oraromatic esters (e.g., methyl or ethyl esters) derived from acidicgroups (e.g., carboxyl) pendent on the compounds of this invention arepreferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy) alkyl esters or[(alkoxycarbonyl)oxy]alkyl esters.

The method of the invention can be practiced using pharmaceuticalformulations containing compounds of the invention administered throughthe skin by an appliance such as a transdermal patch, as described inU.S. Pat. Nos. 5,296,222 and 5,271,940, the disclosures of which areincorporated herein by reference. Lipophilic prodrug derivatives of thecompounds for the formula (II) are particularly well suited fortransdermal absorption administration and delivery systems.

The synthesis of the 1H-indole-3-glyoxylamide compounds may beaccomplished as described European Patent Application No. 95302166.4,Publication No. 0 675 110 (publ., Oct. 4, 1995). The synthesis of theindolizine compounds may be accomplished as described WO 9603383 (Publ.,Feb. 8, 1996). Such synthetic methods also include well-known methods asrecorded in the chemical literature and the procedure illustrated in thefollowing preparative reaction scheme.

The following abbreviations are used throughout the synthesis Schemesand Examples.

Et ethyl Pr propyl t-Bu t-butyl Bn benzyl LAH lithium aluminum hydrideTHF tetrahydrofuran DMF dimethylformamide

(wherein R₁₂, R₁₅, R₁₆ and R₁₇ are as defined above. R₃ is C1-C5 alkyl,aryl, C1-C6 alkoxy, halo, aryloxy, aralkyloxy, nitro, hydroxy, amino,methylamino or dimethylamino. R₅ is hydrogen, C1-C10 alkyl, aryl, C1-C10alkaryl, C1-C10 aralkyl or halo.)

Explanation of Preparative Reaction Scheme 1:

To obtain the glyoxylamides substituted in the 4-position with an acidicfunction through an oxygen atom, the reactions outlined in scheme 1 areused (for conversions 1 through 5, see ref. Robin D. Clark, Joseph M.Muchowski, Lawrence E. Fisher, Lee A. Flippin, David B. Repke, MichelSouchet, Synthesis, 1991, 871-878, the disclosures of which areincorporated herein by reference). The ortho-nitrotoluene, 1, is readilyreduced to the 2-methylaniline, 2, using Pd/C as catalyst. The reductioncan be carried out in ethanol or tetrahydrofuran (THF) or a combinationof both, using a low pressure of hydrogen. The aniline, 2, on heatingwith di-tert-butyl dicarbonate in THF at reflux temperature is convertedto the N-tert-butylcarbonyl derivative, 3, in good yield. The dilithiumsalt of the dianion of 3 is generated at −40 to −20° C. in THF usingsec-butyl lithium and reacted with the appropriately substitutedN-methoxy-N-methylalkanamide. This product, 4, may be purified bycrystallization from hexane, or reacted directly with trifluoroaceticacid in methylene chloride to give the 1,3-unsubstituted indole 5. The1,3-unsubstituted indole 5 is reacted with sodium hydride indimethylformamide at room temperature (20-25° C.) for 0.5-1.0 hour. Theresulting sodium salt of 5 is treated with an equivalent of arylmethylhalide and the mixture stirred at a temperature range of 0-100° C.,usually at ambient room temperature, for a period of 4 to 36 hours togive the 1-arylmethylindole, 6. This indole, 6, is O-demethylated bystirring with boron tribromide in methylene chloride for approximately 5hours (see ref. Tsung-Ying Shem and Charles A Winter, Adv. Drug Res.,1977, 12, 176, the disclosure of which is incorporated herein byreference). The 4-hydroxyindole, 7, is alkylated with an alphabromoalkanoic acid ester in dimethylformamide (DMF) using sodium hydrideas a base, with reactions conditions similar to that described for theconversion of 5 to 6. The α-[(indol-4-yl)oxy]alkanoic acid ester, 8, isreacted with oxalyl chloride in methylene chloride to give 9, which isnot purified but reacted directly with ammonia to give the glyoxlamide10. This product is hydrolyzed using 1N sodium hydroxide in MeOH. Thefinal glyoxylamide, 11, is isolated either as the free carboxylic acidor as its sodium salt or in both forms.

Preparative Reaction Scheme 2-1

26-28 R₁₂ R₂ a: Et Ph b: Et o-Ph—Ph c: Et m-Cl—Ph d: Et m-CF₃—Ph e: Et1-Naphthyl f: cyclo-Pr o-Ph—Ph

(wherein R₁₂, R₁₅, R₁₆ and R₁₇ are as defined above. R₂ is C6-C20 alkyl,C6-C20 alkenyl, C6-C20 alkynyl or carbocyclic radical.)

Explanation of Preparative Reaction Scheme 2-1:

Compound 23 (N. Desideri F. Mama, M. L. Stein, G. Bile, W. Filippeelli,and E. Marmo, Eur. J. Med. Chem. Chim. Ther., 18, 295, (1983)) isO-alkylated using sodium hydride and benzyl chloride to give 24.N-alkylation of 24 by 1-bromo-2-butanone or chloromethylcyclopropylketone and subsequent base catalyzed cyclization gives 25 which isacylated by aroyl halide to give 26. Hydrolysis of the ester function of26 followed by acidification forms an acid which is thermallydecarboxylated to give 27. Reduction of the ketone function of 27 by LAHyields indolizines 28.

Preparative Reaction Scheme 2-2

35-40 R₃ R₄ R₁₂ R₂ a: H H Et Ph d: H H Et o-Ph—Ph g: H H Me Ph h: H H Etm-Cl—Ph i: H H Et m-CF₃—Ph j: H H Et 1-Naphthyl k: H H cyclo-Pr o-Ph—Phl: H H Me cyclo-Hex

(wherein R₂, R₁₂, R₁₅, R₁₆ and R₁₇ are as defined above. R₅ is hydrogenor C1-C6 alkyl.)

Explanation of Preparative Reaction Scheme 2-2:

Sequential treatment of 28 with oxalyl chloride and ammonium hydroxideforms 35 which is debenzylated by hydrogen in the presence of Pd/C togive 36. Indolizines 36 are 0-alkylated using sodium hydride andbromoacetic acid esters to form 37, 38, or 39 which are converted toindolizines 40 by hydrolysis with aqueous base followed byacidification.

Pharmaceutical Formulations

Suitable pharmaceutical formulation of the 1H-indole-3-glyoxylamidecompounds may be made as described European Patent Application No.95302166.4, Publication No. 0 675 110 (publ., Oct. 4, 1995). Suitablepharmaceutical formulation of the indolizine-1-glyoxylamide compoundsmay be made as described WO 9603383 (publ., Feb. 8, 1996). Formulationsmay be obtained by conventional procedures well known in thepharmaceutical art.

The 1H-indole-3-glyoxylamide compound or indolizine-1-glyoxylamidecompound is generally administered as an appropriate pharmaceuticalcomposition which comprises a therapeutically effective amount of1H-indole-3-glyoxylamide compound or indolizine-1-glyoxylamide istogether with a pharmaceutically acceptable diluent or carrier, thecomposition being adapted for the particular route of administrationchosen. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the1H-indole-3-glyoxylamide compound or indolizine-1-glyoxylamide compoundin the formulation and not deleterious to the subject being treated.

Preferably the pharmaceutical formulation is in unit dosage form. Theunit dosage form can be a capsule or tablet itself, or the appropriatenumber of any of these. The quantity of active ingredient in a unit doseof composition may be varied or adjusted from about 0.1 to about 1000milligrams or more according to the particular treatment involved.

The compound can be administered by a variety of routes including oral,aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular,and intranasal.

For the pharmaceutical formulations any suitable carrier known in theart can be used. In such a formulation, the carrier may be a solid,liquid, or mixture of a solid and a liquid. A solid carrier can be oneor more substances which may also act as flavoring agents, lubricants,solubilisers, suspending agents, binders, tablet disintegrating agentsand encapsulating material.

Tablets for oral administration may contain suitable excipients such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate,together with disintegrating agents, such as maize, starch, or alginicacid, and/or binding agents, for example, gelatin or acacia, andlubricating agents such as magnesium stearate, stearic acid, or talc. Intablets the 1H-indole-3-glyoxylamide compound orindolizine-1-glyoxylamide compound is mixed with a carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom about 1 to about 99 weight percent of the 1H-indole-3-glyoxylamidecompound or indolizine-1-glyoxylamide compound.

Sterile liquid form formulations include suspensions, emulsions, syrupsand elixirs. The active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent or a mixture of both.

EXAMPLES

The following Example 1 illustrates the preparation of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, a 1H-indole-3-glyoxylamide compound useful in the practice of themethod of the invention:

Example 1

Preparation of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, a compound represented by the formula:

Part A. Preparation of 2-Ethyl-4-methoxy-1H-indole.

A solution of 140 mL (0.18 mol) of 1.3M sec-butyl lithium in cyclohexanewas added slowly to N-tert-butoxycarbonyl-3-methoxy-2-methylaniline(21.3 g, 0.09 mol) in 250 mL of THF keeping the temperature below −40°C. with a dry ice-ethanol bath. The bath was removed and the temperatureallowed to rise to 0° C. and then the bath replaced. After thetemperature had cooled to −60° C., 18.5 g (0.18 mol) ofN-methoxy-N-methylpropanamide in an equal volume of THF was addeddropwise. The reaction mixture was stirred 5 minutes, the cooling bathremoved and stirred an additional 18 hours. It was then poured into amixture of 300 mL of ether and 400 mL of 0.5N HCl. The organic layer wasseparated, washed with water, brine, dried over MgSO₄, and concentratedat reduced pressure to give 25.5 g of a crude of1-[2-(tert-butoxycarbonylamino)-6-methoxyphenyl]-2-butanone. Thismaterial was dissolved in 250 mL of methylene chloride and 50 mL oftrifluoroacetic acid and stirred for a total of 17 hours. The mixturewas concentrated at reduced pressure and ethyl acetate and water addedto the remaining oil. The ethyl acetate was separated, washed withbrine, dried (MgSO₄) and concentrated. The residue was chromatographedthree times on silica eluting with 20% EtOAc/hexane to give 13.9 g of2-ethyl-4-methoxy-1H-indole.

Analyses for C₁₁H₁₃NO:

Calculated: C, 75.40; H, 7.48; N, 7.99; Found: C, 74.41; H, 7.64; N,7.97.

Part B. Preparation of 2-Ethyl-4-methoxy-1-(phenylmethyl)-1H-indole.

2-Ethyl-4-methoxy-1H-indole (4.2 g, 24 mmol) was dissolved in 30 mL ofDMF and 960 mg (24 mmol) of 60% NaH/mineral oil was added. After 1.5hours, 2.9 mL(24 mmol) of benzyl bromide was added. After 4 hours, themixture was diluted with water and extracted twice with ethyl acetate.The combined ethyl acetate was washed with brine, dried (MgSO₄) andconcentrated at reduced pressure. The residue was chromatographed onsilica gel and eluted with 20% EtOAc/hexane to give 3.1 g (49% yield) of2-ethyl-4-methoxy-1-(phenylmethyl) 1H-indole.

Part C. Preparation of 2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole.

By the method used in Example 1, Part D, in EP Publication No. 0 675110, 3.1 g (11.7 mmol) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indolewas O-demethylated by treating it with 48.6 mL of 1M BBr₃/CH₂Cl₂ to givea material that was chromatographed on silica gel (eluted with 20%EtOAc/hexane) to give 1.58 g (54% yield) of2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole, mp, 86-90° C.

Analyses for C₁₇H₁₇NO:

Calculated: C, 81.24; H, 6.82; N, 5.57; Found: C, 81.08; H, 6.92; N,5.41.

Part D. Preparation of2-[[2-Ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester.

Using the procedure described in Example 1, Part E, in EP PublicationNo. 0 675 110, 2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (1.56 g, 6.2mmol) was treated with 248 mg (6.2 mmol) of 60% NaH/mineral oil and then0.6 mL (6.2 mmol) of methyl bromoacetate. The product was purified bychromatography over silica gel eluting with 20% EtOAc/hexane, to give1.37 g (69% yield) of[[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxyl]acetic acid methyl ester;mp 89-92° C.

Analyses for C₂₀H₂₁NO₃:

Calculated: C, 74.28; H, 6.55; N, 4.33; Found: C, 74.03; H, 6.49; N,4.60.

Part E. Preparation of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid methyl ester.

Using the procedure in Example F, in EP Publication No. 0 675 110, 1.36g (4.2 mmol) of [[2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acidmethyl ester was reacted first with 0.4 mL (4.2 mmol) of oxalyl chlorideand then excess ammonia to give a white solid. This was stirred withethyl acetate and the insoluble material separated and dried to give1.37 g of a mixture of[[3-(2-amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid methyl ester and ammonium chloride. This mixture melted at 172-187°C.

Part F. Preparation of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid.

A mixture of 788 mg (2 mmol) of[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid methyl ester, 10 mL of 1N NaOH and 30 mL of MeOH was heated tomaintain reflux for 0.5 hour, stirred at room temperature for 0.5 hourand concentrated at reduced pressure. The residue was taken up in ethylacetate and water, the aqueous layer separated and made acidic to pH 2-3with 1N HCl. The precipitate was filtered and washed with ethyl acetateto give 559 mg (74% yield) of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, mp 230-234° C.

Analyses for C₂₁H₂₀N₂O₅:

Calculated: C, 65.96; H, 5.80; N, 7.33; Found: C, 66.95; H, 5.55; N,6.99.

The following Example 2 illustrates the preparation of(8-(Carbomethoxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl)glyoxylamide,a indolizine-1-glyoxylamide compound useful in the practice of themethod of the invention:

Example 2

Part A: Preparation of Ethyl 3-benzyloxy-2-pyridineacetate 24

60% Sodium hydride (2.69 g, 66.2 mmol) was added in small portions to asolution of ethyl 3-hydroxy-2-pyridineacetate (23, 12.0 g, 66.2 m mol)(N. Desideri, F. Manna, M. L. Stein, G. Bile, W. Filippeelli, and E.Marmo. Eur. J. Med. Chem. Chim. Ther., 18, 295 (1983)) indimethylformamide (220 ml) at 0° C. The mixture was stirred at 0° C. for50 min. Benzyl chloride (8.4 ml, 72.8 mmol) was added dropwise to themixture, which was stirred overnight. Ethyl acetate was added. Themixture was washed with 5% aqueous sodium hydrogencarbonate and waterand dried over Na₂SO₄. After removing the solvent at reduced pressure,the residue was chromatographed on silica gel eluting with AcOEt:toluene(1:19 to 1:1) to give 16.17 g (90.0% yield) of the titled compound as anoil.

IR ν_(max) (film) 1736, 1446, 1278 cm⁻¹. ¹H NMR (CDCl₃) δ 1.21 (3H, t,J=7.2 Hz), 3.93 (2H, s), 4.14 (2H, q, J=7.2 Hz), 5.10 (2H, s), 7.13-7.22(2H, m), 7.32-7.43 (5H, m), 8.16 (1H, d J=4.0, 3.0 Hz). Analyses: Calc'dfor C₁₆H₁₇NO₃: C, 70.83; H, 6.32; N, 5.16. Found: C, 70.65; H, 6.37; N,5.20.

Part B: Preparation of Ethyl(8-benzyloxy-2-ethylindolizin-1-yl)carboxylate 25a

A mixture of pyridine derivative (24, 15.15 g, 55.8 mmol) sodiumhydrogencarbonate (23.45 g, 279 mmol) and 1-bromo-2-butanone (11.4 ml,113 mmol) in methylethylketone (250 ml) was heated under reflux for 24hours, washed with water and dried over Na₂SO₄. After removing thesolvent at reduced pressure, the residue was chromatographed on silicagel eluting with AcOEt:hexane (1:19 to 1:9) to give 16.66 g, (92.0%yield) of the titled compound as an oil.

IR ν_(max) (film) 1690, 1227, 1092 cm⁻¹. ¹H NMR (CDCl₃) δ 1.15 (3H, t,J=7.2 Hz), 1.26 (3H, t, J=7.5 Hz), 2.82 (2H, q, J=7.5 Hz), 4.11 (2H, q,J=7.2 Hz), 5.16 (2H, s), 6.22 (1H, d, J=7.6 Hz), 6.44 (1H, t, J=7.1 Hz),7.07 (1H, s), 7.27-7.57 (6H, m). Analyses: Calc'd for C₂₀H₂₁NO₃ 0.1H₂O:C, 73.87; H, 6.57; N, 4.31. Found: C, 73.75; H, 6.66; N, 4.30.

Part C: Preparation of Ethyl(8-benzyloxy-2-ethyl-3-(o-phenylbenzoyl)indolizin-1-yl)carboxylate 26b

A mixture of the indolizine (25, 1 eq), o-phenyl benzoyl chloride (2.0eq) and triethylamine (5.0 eq) was heated at 90° C. (bath temp.) for 2-8hours. Ethyl acetate was added. The mixture was washed with dilutehydrochloric acid and water and dried over Na₂SO₄. After removing thesolvent at reduced pressure, the residue was chromatographed on silicagel eluting with AcOEt:hexane (1:2) and recrystallized. 46.0% Yield. mp,110-112° C. (ether-hexane).

Part D: Preparation of 8-Benzyloxy-2-ethyl-3-(o-phenylbenzoyl)indolizine27b

To a solution of the ester (26, 1.0 mmol) in dimethylsulfoxide (10 ml),50% aqueous potassium hydroxide (3 ml) was added. The mixture was heatedat 140° C. for 2-24 hours. After cooling, the mixture was acidified withdilute hydrochloric acid and extracted with ethyl acetate. The extractswere washed with water dried over Na₂SO₄. After removing the solventunder reduced pressure, the residue was purified by recrystallization togive the carboxylic acid. The acid in toluene was heated under refluxfor 1 hour and the solvent was removed by distillation at reducedpressure. The residue was purified by recrystallization to give 27.Quantitative yield.

IR ν_(max) (nujol) 1735, 1597, 742 cm⁻¹.

Part E: Preparation of 8-Benzyloxy-2-ethyl-3-(o-phenylbenzyl)indolizine28b

Compound 27 was treated by the procedure described for the preparationof 4, WO 9603383. Quantitative yield.

IR ν_(max) (CHCl₃) 1525, 1259 cm⁻¹.

Part F: Preparation of(8-Benzyloxy-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl)glyoxylamide 35d

These compounds were prepared according to the procedure described forthe synthesis of compound 8 from compound 4, WO 9603383. 79.0% Yield.

mp, 183-185° C. (ether-hexane).

Part G: Preparation of(2-Ethyl-8-hydroxy-3-(o-phenylbenzyl)indolizin-1-yl)glyoxylamide 36d

These compounds were prepared according to the procedure described forthe synthesis of compound 20 from 19, WO 9603383. 95.0% Yield.

mp, 195-196° C. (dec.) (ether-hexane).

Part H: Preparation of(8-(Carbomethoxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl)glyoxylamide39d

These compounds were prepared according to the procedure described forthe synthesis of compound 21 from 20, WO 9603383. 84% Yield.

mp, 73-75° C. (dec.) (ether-hexane).

Part I: Preparation of(8-(Carboxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl)glyoxylamide40d

1N-Aqueous potassium hydroxide (4 ml) was added to a solution of theester (37-39, 2 mmol) in methanol (21 ml). The solution was stirred atroom temperature for 40 min, washed with ether, acidified with 2N-HCland extracted with ethyl acetate. The extracts were washed with waterand dried over Na₂SO₄. After removing the solvent at reduced pressure,the residue was recrystallized. 93% Yield.

mp, 209-212° C. (dec.) (ether-hexane). IR ν_(max) (nujol) 3316, 1704,1601, 1493 cm⁻¹. ¹H NMR (d₆-DMSO) δ 1.01 (3H, t, J=7.5 Hz), 2.67 (2H, q,J=7.5 Hz), 4.18 (2H, s), 4.71 (2H, s), 6.41 (1H, d, J=7.8 Hz), 6.57-6.59(2H, m), 7.14-7.57 (10H, m), 7.34 (1H, s), 13.09 (1H, br.s). Analyses:Calc'd for C₂₇H₂₄N₂O₅0.3H₂O: C, 70.21; H, 5.37; N, 6.06. Found: C,70.17; H, 5.35; N, 5.98.

The stroke treatment utility of the method of the invention will now beillustrated by the following Example 3 and 4:

Example 3

This example illustrates the effect of[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid (the compound prepared by Example 1, hereinafter called “Ex-1”) oncerebral infarction in a rat focal stroke model.

Experimental protocol:

Wistar male rats weighing 240-260 g were used. The body temperature ofthe animals was maintained at 37.5° C. with a heating pad during theoperation. Anesthesia was induced with 3% halothane in 30% oxygen andmaintained with 1-1.5% halothane in 30% oxygen. A catheter for theadministration of rose bengal and Ex-1 was placed in the femoral vein. Asubtemporal craniotomy was performed using a dental drill under anoperating microscope to open a 3-mm diameter circular bone window,through which photo-irradiation with green light (wave length, 540 nm)was achieved by using a xenon lamp (Umemura et al. Stroke 24, 1077-1082,1993). The head of optic fiber with 3-mm-diameter was placed on thewindow in the skull base, and rose bengal (20 mg/kg) was injectedintravenously. Photo-irradiation on the main trunk of left middlecerebral artery (MCA) was performed for 10 minutes. The incisions wereclosed after the confirmation of thrombotic occlusion. Twenty-four hoursafter the completion of the irradiation, cerebrum was removed underpentobarbital (50 mg/kg i.p.) anesthesia. The cerebrum was coronallysectioned in 1-mm thicknesses from the frontal lobe with a microslicer,and then consecutive slices were stained with triphenyltetrazoliumchloride (TTC). Photographs of the slices were taken. The infarctionvolumes of cerebral cortex and striatum were determined by theintegration of the surfaces of sections and distances between them.Ex-1, dissolved in 0.9% saline, was injected as a bolus (3 mg/kg, i.v.)5 minutes or 2 hours after occlusion of the MCA and then infused (0.5mg/kg/hr, i.v.) until 24 hours after the MCA occlusion. Data areexpressed as ±S.D. Statistical analysis was performed with unpairedStudent's t test or Dunnett's t test. A value of P<0.05 was consideredsignificant.

TABLE 1 (Ex-1 compound activity) PIT-MCAO Ex-1 (3 mg/kg i.v. + 0.5mg/kg/hr i.v.) Infarct volume Control Post-5 min Post-2 hr (mm3) CortexStriatum Cortex Striatum Cortex Striatum Rat No. R1 146.2 63.0 91.3 92.190.6 57.2 R2 145.2 89.3 98.6 84.6 81.2 46.0 R3 168.1 84.2 108.8 71.088.0 69.1 R4 123.0 71.6 137.7 82.4 101.3 50.8 R5 172.3 103.7 78.7 66.2113.3 61.5 R6 113.8 80.1 66.0 40.4 111.2 73.8 R7 138.2 68.7 98.4 65.5 R8168.4 74.7 Mean 146.9 79.4 97.1 71.7 97.6 59.7 S.D. 21.7 13.0 22.8 17.113.1 10.6 t-Test vs. Cont. P < 0.01 None P < 0.01 P < 0.01 Note:PIT-MCAO is photochemically induced thrombosis-middle cerebal arteryocclusion.

Results:

As shown by the test results in Table 1 compound Ex-1 (3 mg/kg i.v.+0.5mg/kg/hr i.v. until 24 hours after the MCA occlusion) significantlyreduced cerebral infarction size, which was observed not only at 5minutes post-treatment but also at 2 hours post-treatment.

Example 4

This example illustrates the effect of(8-(Carbomethoxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl)glyoxylamide(the compound prepared by Example 2, hereinafter called “Ex-2”) oncerebral infarction in a rat focal stroke model

The experiment was carried out in the same method as in Example 3mentioned above other than the following.

Ex-2 (10 or 30 mg/kg, p.o.) was suspended on 0.6% arabic gum solutionand administered 1 hour before or 2 hours after the MCA occlusion.

TABLE 2 (Ex-2 compound activity) PIT-MCAO Ex-2 (p.o.; Post 2 hr) Infarctvolume Control 10 mg/kg 30 mg/kg (mm3) Cortex Cortex Cortex Rat No. R1159.3 124.9 100.3 R2 154.9 91.0 129.5 R3 136.6 80.6 62.9 R4 118.5 112.099.9 R5 122.2 96.9 67.1 R6 161.3 84.8 88.8 Mean 142.1 98.4 91.4 S.D.19.0 17.0 24.5 t-Test vs. Cont. P < 0.01 P < 0.01

PIT-MCAO Ex-2 (p.o.; Pre 1 hr) Infarct volume Control 30 mg/kg (mm3)Cortex Cortex Rat No. R1 104.2 105.4 R2 119.1 83.2 R3 127.5 77.9 R4166.8 76.0 R5 85.8 109.3 R6 100.7 68.0 Mean 117.4 86.6 S.D. 28.3 16.8t-Test vs. Cont. P < 0.05

Result:

As shown by the test results in Table 2 compound Ex-2 (10 or 30 mg/kg,p.o. an orally available indolizine derivative), also significantlyreduced cerebral infarct size regardless of the treatment at 1 hourbefore or at 2 hours after the MCA occlusion.

The following pharmaceutical formulations 1 through 8 are illustrativeonly and are not intended to limit the scope of the invention in anyway. “Active ingredient”, refers to a compound according to formula (I)or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet) Active ingredient 250 Cellulose, microcrystalline400 Silicon dioxide, fumed 10 Stearic acid 5 Total 665

Formulation 3

An aerosol solution is prepared containing the following components:

Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 74.00(Chlorodifluoromethane) Total 100.00

The active compound is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

Tablets, each containing 60 mg of active ingredient, are made asfollows:

Active ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mgPolyvinylpyrrolidone 4 mg (as 10% solution in water) Sodiumcarboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1 mg Total150 mg

The active ingredient, starch and cellulose are passed through a No.45mesh U.S.sieve and the mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No.14 mesh U.S.sieve. The granules so producedare dried at 50° C. and passed through No.18 mesh U.S.sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No.60 mesh U.S.sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

Formulation 5

Capsules, each containing 80 mg of active ingredient, are made asfollows:

Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mgMagnesium stearate 2 mg Total 200 mg

The active ingredient, cellulose, and magnesium stearate are blended,passed through a No.45 mesh U.S.sieve, and filed into hard gelatincapsules in 200 mg quantities.

Formulation 6

Suppositories, each containing 225 mg of active ingredient, are made asfollows:

Active ingredient 225 mg Saturated fatty acid glycerides 2000 mg Total2225 mg

The active ingredient is passed through a No.60 mesh U.S.sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 7

Suspensions, each containing 50 mg of active ingredient per 5 ml dose,are made as follows:

Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified waterto total 5 ml

The active ingredient is passed through a No.45 mesh U.S.sieve and mixedwith the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

Formulation 8

Active ingredient 100 mg Isotonic saline 1000 ml

The solution of the above ingredients generally is administeredintravenously to a subject at a rate of 1 ml per minute.

While the present invention has been illustrated above by certainspecific embodiments, it is not intended that these specific examplesshould limit the scope of the invention as described in the appendedclaims.

What is claimed is:
 1. A method of treatment of a mammal currentlyafflicted with a stroke or previously afflicted with a stroke, saidmethod comprising administering to said mammal a therapeuticallyeffective amount of an N-heterocyclic glyoxylamide compound representedby the formula (I) or a pharmaceutically acceptable salt, solvate, orprodrug derivative thereof:

wherein; E and F are differently C or N; ----- is presence or absence ofa double bond; each X is independently oxygen or sulfur; R₁₁ is selectedfrom groups (a), (b) and (c) where; (a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl,C₇-C₂₀ alkynyl; or carbocyclic radical selected from the groupcycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl,bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl,diphenylethylenyl, phenyl-cyclohexenyl, acenaphthyl, and anthryl,biphenylyl, bibenzylyl and related bibenzylyl homologues represented bythe formula (bb),

 where n is a number from 1 to 8; or (b) is a member of (a) substitutedwith one or more independently selected non-interfering substituentsselected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₇-C₁₂ aralkyl, C₇-C₁₂ alkaryl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C₁-C₆ alkoxy, C₂-C₆alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₁₂ alkoxyalkyl, C₂-C₁₂ alkoxyalkyloxy,C₂-C₁₂ alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino,C₂-C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁-C₆ alkylthio, C₂-C₁₂alkylthiocarbonyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₆haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆ haloalkyl, C₁-C₆hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O-(C₁-C₆ alkyl),benzyloxy, phenoxy, phenylthio, —CHO, amino, amidino, bromo, carbamyl,carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal, thiocarbonyl,and C₁-C₆ carbonyl; where n is from 1 to 8; (c) is the group -(L₁)-R₈₁;where, -(L₁)- is a divalent linking group having the formula;

where, R₈₄ and R₈₅ are each independently selected from hydrogen, C₁-C₁₀alkyl, carbolxy, carbalkoxy, or halo; p is 1 to 5, Z is a bond, —(CH₂)—,—O—, —N(C₁-C₁₀ alkyl)-, —NH—, or —S—; and where R₈₁ is a group selectedfrom (a) or (b); R₁₂ is hydrogen, halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl,C₃-C₄ cycloalkenyl, —O-(C₁-C₂ alkyl), or —S-(C₁-C₂ alkyl); R₁₄ ishydrogen or a group, -(L_(a))-(acidic group) wherein -(L_(a))- isrepresented by the formula;

 where Q is selected from the group —(CH₂)—, —O—, —NH—, and —S—, and R₈₄and R₈₅ are each independently selected from hydrogen, C₁-C₁₀ alkyl,aryl, C₁-C₁₀ alkaryl, C₁-C₁₀ aralkyl, and halo; R₁₅ is hydrogen or agroup, -(La′)-(acidic group) wherein -(La′)- is represented by theformula;

 where r is a number from 1 to 7, s is 0 or 1, and Q is selected fromthe group —(CH₂)—, —O—, —NH—, and —S—, and R₈₄′ and R₈₅′ are eachindependently selected from hydrogen, C₁-C₁₀ alkyl, aryl, C₁-C₁₀alkaryl, C₁-C₁₀ aralkyl, carboxy, carbalkoxy, and halo; provided that atleast one of R₁₄ or R₁₅ must be the group, -(La)-(acidic group) or-(La′)-(acidic group); R₁₆ is hydrogen, carboxyl or ester thereof; R₁₇is selected from hydrogen, non-interfering substituents, selected fromthe group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₇-C₁₂ aralkyl, C₇-C₁₂ alkaryl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl,phenyl, tolyl, xylyl, biphenylyl, C₁-C₆ alkoxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₁₂ alkoxyalkyl, C₂-C₁₂ alkoxyalkyloxy, C₂-C₁₂alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino, C₂-C₁₂alkoxyaminocarbonyl, C₂-C₁₂ alkylamino, C₁-C₆ alkylthio, C₂-C₁₂alkylthiocarbonyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₆haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆ haloalkyl, C₁-C₆hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O-(C₁-C₆ alkyl),benzyloxy, phenoxy, phenylthio, —CHO, amino, amidino, bromo, carbamyl,carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal, thiocarbonyl,and C₁-C₆ carbonyl; where n is from 1 to
 8. 2. A method of treatment ofa mammal currently afflicted with a stroke or previously afflicted witha stroke, said method comprising administering to said mammal atherapeutically effective amount of a 1H-indole-3-glyoxylamide compoundrepresented by the formula (II) or a pharmaceutically acceptable salt,solvate, or prodrug derivative thereof:

wherein each X is independently oxygen or sulfur, R₁₁ is selected fromgroups (a), (b) and (c) where (a) is C₇-C₂₀ all C₇-C₂₀ alkenyl, C₇-C₂₀alkynyl; or carbocyclic radical selected from the group consisting ofcycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl,bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl,diphenylethylenyl, phenyl-cyclohexanyl, acenaphthyl, anthryl,biphenylyl, bibenzylyl and related bibenzylyl homologues represented bythe formula (bb):

 where n is a number from 1 to 8; (b) is a member of (a) substitutedwith one or more independently selected non-interfering substituentsselected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₇-C₁₂ aralkyl, C₇-C₁₂ alkaryl, C₃-C₈ cycloky, C₃-C₈cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C₁-C₆ alkoxy, C₂-C₆alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₁₂ alkoxyalkyl, C₂-C₁₂ alkoxyalkyloxy,C₂-C₁₂ alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino,C₂-C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁-C₆ alkylthio, C₂-C₁₂alkylthiocarbonyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₆,haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆ haloalkyl, C₁-C₆hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O-(C₁-C₆ alkyl),benzyloxy, phenoxy, phenylthio, —CHO, amino, amidino, bromo, carbamyl,carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal, thiocarbonyl,and C₁-C₆ carbonyl; where n is from 1 to 8; and (c) is the group-(L₁)-R₈₁; where -(L₁)- is a divalent linking group having the formula:

where, R₈₄ and R₈₅ are each independently selected from the groupconsisting of hydrogen, C₁-C₁₀ alkyl, carboxy, carbalkoxy, and halo; pis 1 to 5, Z is a bond, —(CH₂)—, —O—, —N(C₁-C₁₀ alkyl)-, —NH—, or —S—;and where R₈₁ is a group selected from (a) or (b); R₁₂ is hydrogen,halo, C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl, —O-(C₁-C₂alkyl), or —S-(C₁-C₂ alkyl); R₁₄ is hydrogen or a group,-(L_(a))-(acidic group) wherein -(L_(a))- is represented by the formula;

 where Q is selected from the group —(CH₂)—, —O—, —NH—, and —S—, and R₈₄and R₈₅ are each independently selected from the group consisting ofhydrogen, C₁-C₁₀ alkyl, aryl, C₁-C₁₀ alkaryl, C₁-C₁₀ aralkyl, and halo;R₁₅ is a hydrogen or a group, -(La′)-(acidic group) wherein -(La)- isrepresented by the formula;

where r is a number from 1 to 7, s is 0 or 1, and Q is selected from thegroup consisting of —(CH₂)—, —O—, —NH—, and —S—, and R₈₄′ and R₈₅′ areeach independently selected from the group consisting of hydrogen,C₁-C₁₀ alkyl, aryl, C₁-C₁₀ alkaryl, C₁-C₁₀ aralkyl, carboxy, carbalkoxy,and halo; provided that at least one of R₁₄ or R₁₅ must be the group,-(La)-(acidic group) or -(La′)-(acidic roup); R₁₆ is hydrogen, carboxylor ester thereof; and R₁₇ is hydrogen or a non-interfering substituentselected from the group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₇-C₁₂ aralkyl, C₇-C₁₂ akaryl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C₁-C₆ alkoxy, C₂-C₆alkenyloxy, C₂-C₆ alkynyloxy, C₂-C₁₂ alkoxyalkyl, C₂-C₁₂ alkoxyalkyloxy,C₂-C₁₂ alkylcarbollyl, C₂-C₁₂ alkylcarbonylamino, C₂-C₁₂ alkoxyamino,C₂-C₁₂ alkoxyaminocarbonyl C₂-C₁₂ alkylamino, C₁-C₆ alkylthio, C₂-C₁₂alkylthiocarbonyl, C₁-C₆ alkylsulflnyl, C₁-C₆ alkylsulfonyl, C₂-C₆haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆ haloalkyl, C₁-C₆hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O-(C₁-C₆ alkyl),benzyloxy, phenoxy, phenylthio, —CHO, amino, amidino, bromo, carbamyl,carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal, thiocarbonyl,and C₁-C₆ carbonyl; where n is from 1 to
 8. 3. A method of treatment ofa mammal currently afflicted with a stroke or previously afflicted witha stroke, said method comprising administering to said mammal atherapeutically effective amount of an indolizine-1-glyoxylamidecompound represented by the formula (III) or a pharmaceuticallyacceptable salt, solvate, or prodrug derivative thereof:

wherein each X is independently oxygen or sulfur: R₁₁ is selected fromgroups (a), (b) and (c) where (a) is C₇-C₂₀ alkyl, C₇-C₂₀ alkenyl,C₇-C₂₀ alkynyl; or carbocyclic radical selected from the groupconsisting of cycloalkyl, cycloalkenyl phenyl, naphthyl norbornanyl,bicycloheptadienyl, tolyl xylyl, indenyl, stilbenyl, terphenylyl,diphenylethylanyl, phenyl-cyclohexenyl, acenaphthyl, anthryl,biphenylyl, bibenzylyl and related bibenzylyl homologues represented bythe formula (bb),

 where n is a number from 1 to 8; (b) is a member of (a) substitutedwith one or more independently selected non-interfering substituentsselected from the group consisting of C₁-C₆ alkyl C₂-C₆ alkenyl, C₂-C₆alkynyl C₇-C₁₂ aralkyl, C₇-C₁₂ alkaryl C₃-C₈ cycloalkyl, C₃-C₈cycloalkenlyl, phenlyl tolyl, xylyl, biphenlylyl, C₁-C₆ alkoxy, C₂-C₆alkenlyloxy, C₂-C₆ alkynyloxy, C₂-C₁₂ alkoxyalkyl, C₂-C₁₂alkoxyalkyloxy, C₂-C₁₂ alkylcarbonyl, C₂-C₁₂ alkylcarbonylamino, C₂-C₁₂alkoxyamino, C₂-C₁₂ alkoxyaminocarbonyl, C₁-C₁₂ alkylamino, C₁-C₆alkylthio, C₂-C₁₂ alkylthiocarbonyl, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, C₂-C₆ haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆haloalkyl, C₁-C₆ hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O-(C₁-C₆alkyl), benzyloxy, phenoxy, phenylthio, —CHO, amino, amidino, bromo,carbamyl, carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro, cyano,cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido,hydroxy, hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal,thiocarbonyl, and C₁-C₆ carbonyl; where n is from 1 to 8; and (c) is thegroup -(L₁)-R₈₁; where, -(L₁)- is a divalent linking group having theformula;

 where,  R₈₄ and R₈₅ are each independently selected from the groupconsisting of hydrogen, C₁-C₁₀ alkyl, carboxy, carbalkoxy, or halo; p is1 to 5, Z is a bond, —(CH₂)—, —O—, —N(C₁-C₁₀ alkyl)-, —NH—, or —S—; andwhere R₈₁ is a group selected from (a) or (b); R₁₂ is hydrogen, halo,C₁-C₃ alkyl, C₃-C₄ cycloalkyl, C₃-C₄ cycloalkenyl, —O-(C₁-C₂ alkyl), or—S-(C₁-C₂ alkyl); R₁₄ is hydrogen or a group, -(La)-(acidic group)wherein -(La)- is represented by the formula;

 where Q is selected from the group —(CH₂)—, —O—, —NH—, and —S—, and R₈₄and R₈₅ are each independently selected from the group consisting ofhydrogen, C₁-C₁₀ alkyl, aryl, C₁-C₁₀ alkaryl, C₁-C₁₀ aralkyl, and halo;R₁₅ is hydrogen or a group, -(La′)-(acidic group) wherein -(La′)- isrepresented by the formula;

 where r is a number from 1 to 7, s is 0 or 1, and Q is selected fromthe group consisting of —(CH₂)—, —O—, —NH—, and —S—, and R₈₄′ and R₈₅′are each independently selected from hydrogen, C₁-C₁₀ alkyl, aryl,C₁-C₁₀ alkaryl, C₁-C₁₀ aralkyl, carboxy, carbalkoxy, and halo; providedthat at least one of R₁₄ or R₁₅ must be the group, -(La)-(acidic group)or -(La′)-(acidic group); R₁₆ is hydrogen, carboxyl or ester thereof;and R₁₇ is hydrogen or a non-interfering substituent selected from thegroup consisting of C₁-C₆ alkyl, C₂-C₆ alkenayl, C₂-C₆ alkynyl, C₇-C₁₂aralkyl, C₇-C₁₂ alkaryl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, phenyl,tolyl, xylyl, biphenylyl, C₁-C₆ alkoxy, C₂-C₆ alkenyloxy, C₂-C₆alkynyloxy, C₂-C₁₂ alkoxcyalkyl, C₂-C₁₂ alkoxyalkyloxy, C₂-C₁₂alkylcarbonyl, C₂-C₁₂ alkylcarbonaylamino, C₂-C₁₂ alkoxyamino, C₂-C₁₂alkoxyaminocarbonyl, C₂-C₁₂ alkylamino, C₁-C₆ alkylthio, C₂-C₁₂alkythiocarbonyl, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₂-C₆haloalkoxy, C₁-C₆ haloalkylsulfonyl, C₂-C₆ haloalkyl, C₁-C₆hydroxyalkyl, —C(O)O(C₁-C₆ alkyl), —(CH₂)_(n)—O-(C₁-C₆ alkyl),benzyloxy, phenoxy, phenylthio, —CHO, amino, amidino, bromo, carbamyl,carboxyl, carbalkoxy, —(CH₂)_(n)—CO₂H, chloro, cyano, cyanoguanidinyl,fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy,hydroxyamino, iodo, nitro, phosphono, —SO₃H, thioacetal, thiocarbonyl,and C₁-C₆ carbonyl; where n is from 1 to
 8. 4. The method of claim 2wherein for the compound of formula (II) both X are oxygen, only one ofR₁₄ or R₁₅ are -(La)-(acidic group) or -(La′)-(acidic group) and the(acidic group) is carboxyl.
 5. A method of treatment of a mammalcurrently afflicted with a stroke or previously afflicted with a stroke,said method comprising administering to said mammal in need of suchtreatment a therapeutically effective amount of an N-heterocyclicglyoxylamide compound or a pharmaceutically acceptable salt, solvate, ora prodrug derivative thereof selected from the group consisting ofcompounds (A) through (GG): (A)[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, (B)dl-2-[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]propanoicacid, (C)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid, (D)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-3-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid, (E)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-4-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]aceticacid, (F)[[3-(2-Amino-1,2-dioxoethyl)-1-[(2,6-dichlorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]aceticacid, (G)[[3-(2-Amino-1,2-dioxoethyl)-1-[(4-fluorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]aceticacid, (H)[[3-(2-Amino-1,2-dioxoethyl)-2-methyl-1-[(1-naphthalenyl)methyl]-1H-indol-4-yl]oxy]aceticacid, (I)[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]aceticacid, (J)[[3-(2-Amino-1,2-dioxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]aceticacid, (K)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]aceticacid, (L)[[3-(2-amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-propyl-1H-indol-4-yl]oxy]aceticacid, (M) [[3-(2-Amino-1,2-dioxoethyl)-2-cyclopropyl1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid, (N)[[3-(2-Amino-1,2-dioxoethyl)-1-([1,1′-biphenyl]-2-ylmethyl)-2-cyclopropyl-1H-indol-4-yl]oxy]aceticacid, (O)4-[[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]butanoicacid, (P) mixtures of (A) through (O), (Q)[8-(Carbomethoxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,(R)[3-Benzyl-8-(carbethoxymethyloxy)-2-ethylindolizin-1-yl]glyoxylamide,(S)[8-(Carbethoxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,(T)[3-Benzyl-8-(carbethoxymethyloxy)-2-methylindolizin-1-yl]glyoxylamide,(U)[8-(Carbethoxymethyloxy)-3-(m-chlorobenzyl)-2-ethylindolizin-1-yl]glyoxylamide,(V)[8-Carbethoxymethyloxy-2-ethyl-3-(1-naphthylmethyl)indolizin-1-yl]glyoxylamide,(W)[3-Benzyl-8-(t-butoxycarbonylmethyloxy)-2-ethylindolizin-1-yl]glyoxylamide,(X)[8-(Carbmethoxymethyloxy)-2-ethyl-3-(m-trifluoromethylbenzyl)indolizin-1-yl]glyoxylamide,(Y)[8-(Carbmethoxymethyloxy)-2-cyclopropyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,(Z) [3-Benzyl-8-(carboxymethyloxy)-2-ethylindolizin-1-yl]glyoxylamide,(AA)[8-(Carboxymethyloxy)-2-ethyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,(BB) [3-Benzyl-8-(carboxymethyloxy)-2-methylindolizin-1-yl]glyoxylamide,(CC)[8-(Carboxymethyloxy)-3-(m-chlorobenzyl)-2-ethylindolizin-1-yl]glyoxylamide,(DD)[8-(Carboxymethyloxy)-2-ethyl-3-(m-trifluoromethylbenzyl)indolizin-1-yl]glyoxylamide,(EE)[8-Carboxymethyloxy-2-ethyl-3-(1-naphthylmethyl)indolizin-1-yl]glyoxylamide,(FF)[8-(Carboxymethyloxy)-2-cyclopropyl-3-(o-phenylbenzyl)indolizin-1-yl]glyoxylamide,(GG) mixtures of (Q) through (FF).
 6. A method of treatment of a mammalcurrently afflicted with a stroke or previously afflicted with a stroke,said method comprising administering to said mammal in need of suchtreatment a therapeutically effective amount of an N-heterocyclicglyoxylamide compound selected from the formula:

or a prodrug derivative thereof.
 7. The method of claim 1 whereintreatment is of a mammal currently afflicted with a stroke, theadministering is via a parenteral route and the therapeuticallyeffective amount is a neuronal cell protecting amount.
 8. The method ofclaims 1 wherein the administering is carried out within 6 hours of theonset of the stroke.
 9. The method of claims 1 wherein the compositionis administered intravenously.
 10. The method of claims 1 wherein thecompound is administered orally.
 11. The method of claims 1 whereintreatment is of a mammal previously afflicted with an ischemic event andthe compound is administered in an amount of from 0.01 mg/kg/day to 1000mg/kg/day.
 12. The method of claims 1 wherein the therapeuticallyeffective amount of the compound is in the form of a pharmaceuticalformulation comprising the compound and a suitable carrier or excipienttherefor.
 13. The method of claim 3 wherein for the compound of formula(III) both X are oxygen, only one of R₁₄ or R₁₅ are -(L_(a))-(acidicgroup) or -(La′)-(acidic group) and the (acidic group) is carboxyl. 14.The method of claim 2, wherein treatment is of a mammal currentlyafflicted with a stroke, the administering is via a parenteral route andthe therapeutically efective amount is a neuronal cell protectingamount.
 15. The method of claim 3, wherein treatment is of a mammalcurrently afflicted with a stroke, the administering is via a parenteralroute and the therapeutically efective amount is a neuronal cellprotecting amount.
 16. The method of claim 4, wherein treatment is of amammal currently afflicted with a stroke, the administering is via aparenteral route and the therapeutically efective amount is a neuronalcell protecting amount.
 17. The method of claim 5, wherein treatment isof a mammal currently afflicted with a stroke, the administering is viaa parenteral route and the therapeutically efective amount is a neuronalcell protecting amount.
 18. The method of claim 6, wherein treatment isof a mammal currently afflicted with a stroke, the administering is viaa parenteral route and the therapeutically efective amount is a neuronalcell protecting amount.
 19. The method of claim 2, wherein theadministering is carried out within 6 hours of the onset of the stroke.20. The method of claim 3, wherein the administering is carried outwithin 6 hours of the onset of the stroke.
 21. The method of claim 4,wherein the administering is carried out within 6 hours of the onset ofthe stroke.
 22. The method of claim 5, wherein the administering iscarried out within 6 hours of the onset of the stroke.
 23. The method ofclaim 6, wherein the administering is carried out within 6 hours of theonset of the stroke.
 24. The method of claim 2, wherein the compositionis administered intravenously.
 25. The method of claim 3, wherein thecomposition is administered intravenously.
 26. The method of claim 4,wherein the composition is administered intravenously.
 27. The method ofclaim 5, wherein the composition is administered intravenously.
 28. Themethod of claim 6, wherein the composition is administeredintravenously.
 29. The method of claim 2, wherein the composition isadministered orally.
 30. The method of claim 3, wherein the compositionis administered orally.
 31. The method of claim 4, wherein thecomposition is administered orally.
 32. The method of claim 5, whereinthe composition is administered orally.
 33. The method of claim 6,wherein the composition is administered orally.
 34. The method of claim2, wherein the treatment is of a mammal previously afflicted with anischemic event and the compound is administered in an amount of from0.01 mg/kg/day to 1000 mg/kg/day.
 35. The method of claim 3, wherein thetreatment is of a mammal previously afflicted with an ischemic event andthe compound is administered in an amount of from 0.01 mg/kg/day to 1000mg/kg/day.
 36. The method of claim 4, wherein the treatment is of amammal previously afflicted with an ischemic event and the compound isadministered in an amount of from 0.01 mg/kg/day to 1000 mg/kg/day. 37.The method of claim 5, wherein the treatment is of a mammal previouslyafflicted with an ischemic event and the compound is administered in anamount of from 0.01 mg/kg/day to 1000 mglkglday.
 38. The method of claim6, wherein the treatment is of a mammal previously afflicted with anischemic event and the compound is administered in an amount of from0.01 mg/kg/day to 1000 mg/kg/day.
 39. The method of claim 2, wherein thetherapeutically effective amount of the compound is in the form of apharmaceutical formulation comprising the compound and a suitablecarrier or excipient therefor.
 40. The method of claim 3, wherein thetherapeutically effective amount of the compound is in the form of apharmaceutical formulation comprising the compound and a suitablecarrier or excipient therefor.
 41. The method of claim 4, wherein thetherapeutically effective amount of the compound is in the form of apharmaceutical formulation comprising the compound and a suitablecarrier or excipient therefor.
 42. The method of claim 5, wherein thetherapeutically effective amount of the compound is in the form of apharmaceutical formulation comprising the compound and a suitablecarrier or excipient therefor.
 43. The method of claim 6, wherein thetherapeutically effective amount of the compound is in the form of apharmaceutical formulation comprising the compound and a suitablecarrier or excipient therefor.